The overall goal of this project is to determine the potential role of Death Receptor 5 (DR5)-mediated apoptosis in human autoimmune disease and to evaluate the therapeutic potential of targeting DR5 with agonistic monoclonal antibodies, as selective immunosuppressive and anti-inflammatory agents for human autoimmune disease. The central hypothesis is that autoantigen-activated T cells, B cells, other inflammatory cells selectively express increased levels of DR5, and are susceptible to DR5-mediated apoptosis. As DR5-mediated apoptosis represents a critical alternative pathway to activation-induced cell death (AICD) of immune cells, the specific targeting of DR5 with an agonistic monoclonal antibody such as TRA-8 would facilitate AICD of autoantigen-activated immune cells, thereby leading to a selective inhibition of autoimmune responses with minimal impairment of normal immune responses. The feasibility of this project is based on our successful development of a panel of murine monoclonal antibodies selectively targeting DR5 and DR4. Our previous data support the targeting of DR5 in activated blood B and T cells. This project will test whether DR5 is expressed and functional on cells involved in tissue-directed immunity, both locally and systemically. This will determine the therapeutic potential of specific targeting of DR5 for treatment of tissue-specific human autoimmune disease. We will focus on two common human autoimmune diseases, type 1 diabetes and rheumatoid arthritis, to determine whether autoantigen-specific T cells and inflammatory cells selectively express high levels of DR5 and are susceptible to DR5-mediated apoptosis. The therapeutic potential of TRA-8 will be determined by its ability to selectively eliminate the pathogenic immune cells that are involved in autoimmune diseases. Finally, in collaboration with Dr. Thomas, PI of Project 3, we will use a nonhuman primate skin allograft model to investigate the mechanism anti-DR5 in immunosuppression and possible tolerance induction to tissue antigens. The elucidation of a role for DR5-mediated apoptosis in human autoimmune disease would not only increase our understanding to the pathogenesis of autoimmune disease but also help to develop a more effective therapy for a range of autoimmune diseases.